DE3913245A1 - PYRIDONE CARBONIC ACID DERIVATIVES AND THE SALTS THEREOF, METHOD FOR THE PRODUCTION THEREOF AND ANTIBACTERIAL AGENTS WITH A CONTENT THEREOF - Google Patents

Description

The invention relates to new pyridonecarboxylic acid derivatives with substituted or unsubstituted cyclopropyl group in the 10-position of pyridobenzoxazine, pyridobenzothiazine or pyridoquinoxaline and salts thereof, a process for their manufacture and antibacterial Means containing the same.

Ofloxacin is widely used clinically as a synthetic antibacterial agent from pyridobenzoxazine Type used. The antibacterial effectiveness of this  However, the active ingredient is not completely satisfactory. In particular, the active ingredient does not have a satisfactory one Effect in the treatment of P. aeruginosa Infection, which is a stubborn disease acts.

It is therefore aimed at synthetic antibacterial Develop means that are not only against gram-negative Bacteria including P. aeruginosa but also are effective against gram-positive bacteria, a broad one antibacterial spectrum show an excellent Have solubility and high blood concentration result and which are highly secure (i.e., extreme have minor side effects on the central nervous system).

As a result of extensive research, it is the inventors managed to develop new pyridonecarboxylic acid derivatives and Provide salts with which the above mentioned Problems can be solved.

It is therefore an object of the present invention new pyridonecarboxylic acid derivative and a salt thereof with excellent properties available too ask, e.g. B. with a strong antibacterial activity not just against gram negative bacteria including P. aeruginosa, but also against gram-positive Bacteria, especially against antibiotics resistant bacteria, and that with oral or parenteral Administration results in a high blood concentration and can be used with high security.  

It is also an object of the invention to provide a method for Production of a new pyridonecarboxylic acid derivative or to create a salt of the same.

It is also an object of the invention to provide an antibacterial To create funds in the treatment bacterial infections is useful and which one new pyridonecarboxylic acid derivative or a salt thereof as an active ingredient.

Other objects and advantages of the present invention result from the following description.

According to the invention, a pyridonecarboxylic acid derivative is the following general formula (I) or a salt thereof created

where R¹ represents a hydrogen atom or a carboxyl Protection group stands; R² is a hydrogen atom, a halogen atom, an alkoxy group, a protected or unprotected Hydroxyl group, a protected or unprotected Amino group, a protected or unprotected lower alkylamino group or represents a di-lower alkylamino group; R³ represents at least one group from the group consisting of hydrogen atoms, lower alkyl groups, protected or unprotected amino groups, protected or unprotected lower alkylamino groups,  Di-lower alkylamino groups, protected or unprotected carboxyl groups, protected or unprotected Amino-lower alkyl groups, protected or unprotected lower alkylamino lower alkyl groups, di lower alkylamino lower alkyl groups and protected or unprotected hydroxy lower alkyl groups; R⁴ at least represents a group selected from the Group consisting of hydrogen atoms, lower alkyl groups, Halogeno-lower alkyl groups, protected or unprotected hydroxy-lower alkyl groups, lower alkylidene groups and groups related to the carbon atom, to which R⁴ is bound, a cycloalkane ring form; X represents a halogen atom; and A for an oxygen or sulfur atom or a lower alkyl substituted one or unsubstituted imino group.

Unless otherwise stated, the term "halogen atom" includes z. B. a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; the term "alkyl group" means a C _1-10 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, octyl or the like; the term "lower alkyl group" means a C _1-5 alkyl group from the above-mentioned alkyl groups; the term "alkoxy group" means an -O-alkyl group (the alkyl is a C _1-10 alkyl group); the term "lower alkylamino group" means a C _1-5 alkylamino group such as methylamino, ethylamino, propylamino or the like; the term "di-lower alkylamino group" means a di-C _1-5 alkylamino group such as dimethylamino or the like; the term "amino-lower alkyl group" means an amino-C _1-5 alkyl group such as aminomethyl, aminoethyl, aminopropyl or the like; the term "lower alkylamino lower alkyl group" means a C _1-5 alkylamino-C _1-5 alkyl group such as methylaminomethyl, methylaminoethyl, ethylaminomethyl, methylaminopropyl, propylaminoethyl or the like; the term "di-lower alkylamino-lower alkyl group" means a di-C _1-5 alkylamino-C _1-5 alkyl group such as dimethylaminomethyl, diethylaminomethyl, diethylaminoethyl, dimethylaminopropyl or the like; the term "hydroxy-lower alkyl group" means a hydroxy-C _1-5 alkyl group such as hydroxymethyl, hydroxymethyl, hydroxypropyl or the like; the term "halogen-lower alkyl group" means a halogen C _1-5 alkyl group such as chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, chloroethyl, dichloroethyl, trichlorethyl, chloropropyl or the like; the term "lower alkylidene group" means a C _1-5 alkylidene group such as methylene, ethylidene, propylidene, isopropylidene or the like; and the term "cycloalkane ring" means a C _3-6 cycloalkane ring such as cyclopropane, cyclobutane, cyclopentane, cyclohexane or the like.

The invention is explained in detail below.

In the compound of the general formula (I) or a Salt thereof includes the carboxyl protecting group for R1 and R³, for example, which removes ester-forming groups can be by catalytic reduction, chemical Reduction or other treatments under mild Conditions; ester-forming groups living in a Body can be easily removed; organic Silyl-containing groups, organic, phosphorus-containing Groups and organic groups containing tin,  which is easily achieved by treatment with water or an alcohol can be removed; as well as various others well known ester forming groups, such as those in the JP-OS 80 665/84 are described.

In the definitions of R² and R³, the protecting groups include for amino groups, lower alkylamino groups, amino lower alkyl groups and lower alkylamino lower alkyl groups those traditionally used for this Can be used like formyl, acetyl, benzyl and other conventional amino protecting groups, such as those in the JP-OS 80 665/84 are described.

In the definitions of R², R³ and R⁴ include the Protecting groups for hydroxyl groups and hydroxy-lower alkyl groups such as those conventionally used for this Purpose used, e.g. B. conventional hydroxyl Protecting groups according to JP-OS 80 665/84, such as an organic Silyl group easily by treatment with Water or an alcohol can be removed Formyl group, an acetyl group, a benzyl group or the like.

The salt of the compound of the general formula (I) comprises conventional salts on basic groups such as an amino group and the like, and on acidic groups such as a hydroxyl group, a carboxyl group and the like. The salts on the basic group include, for example, salts with mineral acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid and the like; Salts with organic carboxylic acids such as tartaric acid, formic acid, citric acid, trichloroacetic acid, trifluoroacetic acid and the like; Salts with sulfonic acid such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, naphthalenesulfonic acid and the like. The salts on the acidic group include, for example, salts with alkali metals such as sodium, potassium and the like; Salts with alkaline earth metals such as calcium, magnesium and the like; Ammonium salts; and salts with nitrogen-containing organic bases, such as trimethylamine, triethylamine, tributylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl- β- phenethylamine, 1-ephenamine , N, N'-dibenzylethylenediamine and the like.

If the one represented by the general formula (I) Compound or a salt of the same isomers (e.g. optical isomers, geometric isomers, tautomers and the like), all of these isomers are of the present Invention includes. The invention also includes all crystal forms, solvates and hydrates of compounds of formula (I) and their salts.

The following are the antibacterial activities and acute toxicities of typical compounds of the present invention specified.

1. Antibacterial activity Test procedure

According to the standard method of Japan Society of Chemotherapy [Chemotherapy, 29 (1), 76-79 (1981)] becomes one Bacterial solution obtained by culturing in 20 hours Heart Infusion Broth (manufactured by Eiken-Kagaku) 37 ° C was obtained on a cardiac infusion agar containing  a drug, vaccinated and cultured at 37 ° C for 20 h. The growth of the bacteria is then observed. This way the minimum concentration determined at which the growth of the bacteria inhibits becomes; this value is given as MIC (µg / ml). The amount of inoculated bacteria is 10⁴ cells / plate (10⁶ cells / ml). The MIC values of the The following test compounds are shown in Table 1.

The asterisk in Table 1 means β- lactamase producing bacteria.

Test connections

• 1. 10- (1-aminocyclopropyl) -9-fluoro-3-methyl-7-oxo 2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid hydrochloride
• 2. 8-amino-10- (1-aminocyclopropyl) -9-fluoro-3-methyl- 7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine- 6-carboxylic acid hydrochloride
• 3. 10- (1-aminocyclopropyl) -8,9-difluoro-3-methyl-7- oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazin-6- carboxylic acid hydrochloride
• 4. 10- (1-aminocyclopropyl) -9-fluoro-8-hydroxy-3-methyl- 7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine- 6-carboxylic acid hydrochloride
• 5. (S) -10- (1-aminocyclopropyl) -9-fluoro-3-methyl-7- oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazin-6- carboxylic acid hydrochloride
• 6. 10- (1-aminocyclopropyl) -9-fluoro-3-fluoromethyl-7- oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazin-6- carboxylic acid hydrochloride
• 7. (S) -10- (1-aminocyclopropyl) -3-ethyl-9-fluoro-3-methyl-7- oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazin-6- carboxylic acid hydrochloride  
• 8. 10- (1-aminocyclopropyl) -9-fluoro-3-methylene-7-oxo 2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid hydrobromide
• 9. 10 ′ - (1-aminocyclopropyl) -9′-fluoro-7′-oxospiro- (cyclopropane-1,3 ′ (2′H) - [7H] pyrido [1,2,3-de] [1,4] benzoxazine) -6'-carboxylic acid hydrochloride
• 10. (S) -10- (1-amino-2-methylcyclopropyl) -9-fluoro-3- methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine- 6-carboxylic acid hydrochloride
• 11. (S) -10- [1- (N-methylamino) cyclopropyl] -9-fluorine 3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazin-6-carboxylic acid hydrochloride

Control compound (ofloxacin)

(±) -9-fluoro-2,3-dihydro-3-methyl-10- (4-methyl-1- piperazinyl) -7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazin- 6-carboxylic acid.  

2. Acute toxicity

A test compound becomes a group of three male ICR strain mice each weighing 22 ± 1 g administered intravenously to acute toxicity to investigate. The test compound is in a 0.1N aqueous sodium hydroxide solution and the resulting Solution is used.

It is found that in Test Compound No. 5 the 50% lethal dose (LD₅₀) is over 1000 mg / kg.

The following is the process for the preparation of the invention Connections explained.

The connection according to the invention can, for example, according to the following production route.

R¹, R³, R⁴, A and X have the meaning given above; R ^1a represents the same carboxyl protecting group as in the definition of R¹; R ^{2a represents} a hydrogen atom or the same halogen atom as in the definition of R²; R ^2b represents the same alkoxy group or protected or unprotected hydroxyl group as in the definition of R²; R ^2c represents the same protected or unprotected amino group, protected or unprotected lower alkylamino group or di-lower alkylamino group as in the definition of R²; and R⁵ represents a hydrogen atom or the same amino protecting group as in the definition of R² and R³.

The salts of the compounds of the general formulas (II), (III), (IV), (V), (VI), (VII), (VIII), (Ia), (Ib) and (Ic) include the same salts as those of the compounds of the general formula (I).

The following is each step of the above production path explained.

(1) A compound of the general formula (III) or a salt thereof can be obtained by using one Compound of general formula (II) or a salt the same a keto esterification reaction per se subject known manner.

(i) For example, the carboxyl group becomes one Compound of general formula (II) or a salt the same with a halogenating agent such as thionyl chloride or the like, converted to an acid halide; then the acid halide is mixed with a metal salt (e.g. Sodium salt or ethoxymagnesium salt) of a malonic acid diester  implemented; and then the resulting Product of partial removal of carboxyl Protecting group and decarboxylation with p-toluenesulfonic acid in an aqueous solvent or with trifluoroacetic acid subjected to a connection of general To obtain formula (III) or a salt thereof.

That in the reaction between the acid halide and the Metal salt of a malonic acid diester used solvent can be any solvent as long as it does not adversely affect the reaction. Are included e.g. B. aromatic hydrocarbons, such as benzene, toluene, Xylene and the like; Ethers, such as dioxane, tetrahydrofuran, Diethyl ether and the like; halogenated hydrocarbons, such as methylene chloride, chloroform, dichloroethane and the like; as well as amides, such as N, N-dimethylformamide, N, N-dimethylacetamide and the like. These solvents can either be used individually or used in a mixture of two or more will.

The metal salt of a malonic diester is in a Amount of at least 1 mol and preferably 1 to 3 mol / Moles of acid halide of the compound of the general formula (II) used.

This reaction can generally be at -50 to 100 ° C be carried out for 5 minutes to 30 hours.

(ii) Alternatively, the compound of general Formula (III) or a salt thereof, for example according to the in Angew. Chem. Int. Ed. Engl. Volume 18, p. 72 (1979) described method can be obtained. That is, the Carboxyl group of a compound of the general formula (II) or a salt thereof is converted into an active acid amide  converted with, for example, N, N'-carbonyldiimidazole; and the active acid amide is mixed with a magnesium salt of a malonic acid monoester to form a Compound of general formula (III) or a salt the same implemented.

That in the reaction between the active acid amide and used the magnesium salt of a malonic acid monoester Solvent can be any solvent as long as it does not adversely affect the reaction. Includes are, for example, the same solvents as given above under (1) (i).

The amount of N, N'-carbonyldiimidazole and the amount of magnesium salt of a malonic acid monoester used is in each case at least 1 mole and preferably 1 to 2 mol / mol compound of the general formula (II) or a salt thereof.

This reaction can usually be at 0 to 100 ° C, preferably 10 to 80 ° C, carried out for 5 min to 30 h will.

(2) (i) A compound of the general formula (V) or a salt thereof can be reacted with the compound of the general formula (III) or a salt the same with methyl or ethyl orthoformate in acetic anhydride and subsequent implementation of the resulting Product with a general connection Formula (IV) or a salt thereof can be obtained. [In this case, if there is an optically active connection of the general formula (IV) or a salt thereof is used, an optically active pyridonecarboxylic acid Derivative of the general formula (I) can be obtained.]  

The solvent to be used in this reaction can be any solvent as long as it is the Implementation not adversely affected. Are included, for example aromatic hydrocarbons, such as benzene, Toluene, xylene and the like; Ethers, such as dioxane, tetrahydrofuran, Anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; Alcohols, such as methanol, ethanol, Propanol and the like; halogenated hydrocarbons, such as methylene chloride, chloroform, dichloroethane and the like; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide and the like; and sulfoxides such as dimethyl sulfoxide and The like. These solvents can be used individually or in a mixture can be used from two or more.

The amount of methyl or ethyl orthoformate used is at least 1 mole, and preferably about 1 to 10 mol / mol compound of the general formula (III) or a salt of the same. This implementation can usually at 0 to 150 ° C, preferably 50 to 150 ° C, during 20 minutes to 50 hours.

In the subsequent implementation with the connection of the general formula (IV) or a salt thereof this compound or a salt thereof in an amount of at least 1 mol / mol compound of the general formula (III) or a salt thereof, and the Reaction can usually be at 0 to 100 ° C, preferably 10 to 60 ° C, take 20 min to 30 h.

(ii) Alternatively, the compound of general Formula (V) or a salt thereof can be obtained by reacting the compound of the general formula (III) or a salt thereof with an acetal,  such as N, N-dimethylformamide dimethylacetal, N, N-dimethylformamide diethylacetal or the like, and subsequent ones Implementation of the resulting product with the connection of the general formula (IV) or a salt thereof. [In this case, when using an optically active Compound of general formula (IV) or one Salt thereof an optically active pyridonecarboxylic acid Derivative of the general formula (I) can be obtained.]

The solvent to be used in this reaction can be any solvent as long as it is the Implementation not adversely affected. Are included, for example the same solvents as above (2) (i) mentioned.

The amount of acetal to be used is at least 1 mole, and preferably about 1.0 to 5.0 moles / mole of compound of the general formula (III) or a salt the same.

The reaction can usually be at 0 to 100 ° C, preferably 50 to 85 ° C, take 20 min to 50 h.

In the subsequent implementation with the connection of the general formula (IV) or a salt thereof this compound or a salt thereof in an amount of at least 1 mol / mol compound of the general formula (III) or a salt thereof, and the reaction can usually at 0 to 100 ° C, preferably 10 to 60 ° C for 20 minutes to 30 hours.  

(3) A compound of the general formula (VI) or a salt thereof can be obtained by using the Compound of general formula (V) or a salt thereof a ring closure reaction in the presence or absence a metal fluoride or a base.

The solvent used in this reaction can be a be any solvent as long as it's the reaction not adversely affected, and includes z. B. amides, such as N, N-dimethylformamide, N, N-dimethylacetamide and the like; Ethers, such as dioxane, anisole, diethylene glycol dimethyl ether, Dimethyl cellosolve and the like; and sulfoxides, such as di- methyl sulfoxide and the like. These solvents can used individually or in a mixture of two or more will.

Any metal fluoride used in this reaction includes e.g. As sodium fluoride, potassium fluoride or The like. The base optionally used comprises, for. B. sodium bicarbonate, Potassium carbonate, potassium tert-butoxide, Sodium hydride and the like. The amount to be used of metal fluoride or base is at least 1 mol and preferably 1.0 to 1.5 mol / mol compound of the general Formula (V) or a salt thereof.

This reaction can usually take place at 0 to 180 ° C 5 minutes to 30 hours.

(4) (i) A compound of the general formula (Ia) or a salt thereof can be obtained by the compound of general formula (VI) or a salt same a ring closure reaction in the presence or absence a metal fluoride or a base.  

This reaction can take place under the same conditions as mentioned in (3) above.

(ii) Alternatively, the compound of general Formula (Ia) or a salt thereof are prepared, by using the compound of the general formula (V) or a salt thereof in a ring closure reaction in the presence or absence of a metal fluoride or one Base undergoes. The amount of metal fluoride to use or base is at least 2 moles / mole of compound of the general formula (V) or a salt thereof. This reaction can usually take place at 0 to 180 ° C 5 minutes to 30 hours.

(5) A compound of the general formula (Ib) or a salt thereof can be obtained by reacting the compound of the general formula (Ia) in which R ^{2a represents} a halogen atom or a salt thereof with an alcohol of the general formula (VII) or a salt thereof in the presence or absence of a base.

The solvent to be used in this reaction can be any solvent as long as it is the Implementation not adversely affected. Are z. B. aromatic hydrocarbons, such as benzene, toluene, Xylene and the like; Ethers, such as dioxane, tetrahydrofuran, Diethyl ether and the like; halogenated hydrocarbons, such as methylene chloride, chloroform, dichloroethane and the like; Nitriles such as acetonitrile and the like; as well as amides, such as N, N-dimethylformamide, N, N-dimethylacetamide and The like. These solvents can either be used individually or use in a mixture of two or more.  

Any base used in this reaction includes e.g. B. sodium, potassium tert-butoxide, sodium hydride and the like.

The amount of alcohol of the general formula (VII) or a salt thereof to be used and the amount of the base which may be used is in each case at least 1 mol / mol of a compound of the general formula (Ia) in which R ^{2a is} a halogen atom or a salt thereof. This reaction can usually be carried out at 0 to 150 ° C for 10 minutes to 20 hours.

(6) A compound of the general formula (Ic) or a salt thereof can be obtained by reacting the compound of the general formula (Ia), wherein R ^{2 is} a halogen atom, or a salt thereof with an amine of the general formula (VIII) or a salt can be obtained in the presence or absence of a base.

The solvent to be used in this reaction can be any solvent as long as it is the Reaction is not adversely affected, and includes z. B. the same solvents as mentioned in (5) above. Any base used in this reaction includes e.g. B. organic or inorganic bases, such as Triethylamine, diisopropylethylamine, 1,8-diazabicyclo- [5.4.0] undec-7-ene (DBU), pyridine, potassium tert-butoxide, Potassium carbonate, sodium carbonate, sodium hydride and the like.

The amount of amine of the general formula to be used (VIII) or a salt thereof is preferably 2 to 10 mol / mol compound of the general formula (Ia) or a salt of it. The amount of amine of the general  Formula (VIII) or a salt thereof can be by appropriate use of a base can be reduced. This reaction can generally at 0 to 150 ° C, preferably 15 to 100 ° C, take 5 minutes to 30 hours.

The compound of general formula (I) or a salt the same can be converted into another in a manner known per se Compound of general formula (I) or a salt the same as by oxidation, reduction, Rearrangement, substitution, halogenation, dehydration, Hydrolysis or the like. Or by a appropriate combination of such measures.

Of the compounds of the general formulas (II), (III), (IV), (V), (VI), (VII) and (VIII) can be those which an amino group, a hydroxyl group or a carboxyl group have been obtained by using this Protect the group beforehand with a conventional protective group and after the implementation the protective group on known per se Way away.

The compound of general formula (II) or a Salt thereof, which is used as a raw material in the manufacture serves the compound of the invention a new connection and can, for example, according to following production route.  

In the above production route, R¹, R ^1a , R ^2a and X have the meanings given above; R ^1b represents the same carboxyl protecting group as in the definition of R¹; R ^{3a represents} a hydrogen atom or the same protected or unprotected amino group, protected or unprotected lower alkylamino group, di-lower alkylamino group, protected or unprotected amino lower alkyl group, protected or unprotected lower alkylamino lower alkyl group, di-lower alkylamino lower alkyl group or protected or unprotected hydroxy lower alkyl group as in the definition from R³; R ^{3b represents} the same lower alkyl group as in the definition of R³; and R ^{3c represents} a hydrogen atom or the same lower alkyl group as in the definition of R³.

In each of the compounds of the general formulas (X) and (XI) and their salts, two R ^1b s can be the same or different.

The salts of the compounds of the general formulas (IX), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (IIa), (IIb) and (IIc) include the same salts as those of the compound of general formula (I).

The salts on the active methylene of the compounds of the general formulas (X) and (XII) include salts with Alkali metals such as sodium, potassium, lithium and the like.

A compound of the general formula (XII) or a Salt thereof can be obtained by reacting one Compound of general formula (IX) or one Salt thereof with a compound of the general formula (X) or a salt thereof according to that in U.S. Patent  35 90 036 described method to connect them of the general formula (XI) or a salt thereof to convict. Then this connection or a salt thereof a reaction to remove the Protecting group and decarboxylation in a conventional manner subjected and subsequently a carboxyl protecting group introduced into the resulting product.

The compound of general formula (XII) or a Salt thereof can be used in a compound of general Formula (XIII) or a salt thereof according to the in Chem. Ber., Volume 99, p. 2407 (1966) will.

The compound of general formula (XIII) or a Salt thereof can be used in a compound of general Formula (XIV) or a salt thereof by reacting the the former can be transferred with a diazoalkane.

A compound of the general formula (IIb) or a Salt thereof can be obtained by using the compound of the general formula (XIII) or a salt thereof a deprotection reaction and one Subjects decarboxylation reaction in a conventional manner. This gives a connection of the general Formula (XVI) or a salt thereof. This connection or a salt thereof then becomes a 1,3-dipolar Subjected to addition reaction with a diazoalkane as well nitrogen elimination by heating.

Alternatively, the compound of the general formula (IIb) or a salt thereof by reacting the Compound of general formula (XIII) or one Salt thereof or the compound of the general formula  (XVI) or a salt thereof with trimethylsulfoxonium in the presence of a base such as sodium hydride or the like., Which are obtained in a compound of general Formula (XV) or a salt thereof converted becomes. Then this compound or a salt of which a reaction to remove the protective group and decarboxylation by a conventional method subject.

A compound of the general formula (IIa) or a Salt thereof can be obtained by using a compound of the general formula (XV) or a salt thereof undergoes a known reaction, such as removal of the Protecting group, reduction, amination, Curtius reaction, Alkylation or the like

A compound of the general formula (XVIII) or a Salt thereof can be obtained by using the compound of the general formula (XVI) or a salt thereof subject to bromination or chlorination, then that resulting product with a base such as 1,8-diazabicyclo [5,4,0] undec-7-en (DBU) and the like finally the resulting product with a compound of the general formula (X) or a salt thereof converts them into a compound of the general formula (XVII) or a salt thereof. Then one subjects this compound or a salt thereof a deprotection reaction, or Decarboxylation using conventional methods to them into a compound of the general formula (XVIII) or convert a salt thereof. A connection of the general formula (IIc) or a salt thereof can be obtained by connecting the general Formula (XVIII) or a salt thereof is a known one  Reaction, such as removal of the protective group, reduction, Amidation, Curtius reaction, alkylation or the like, or a suitable combination of these measures.

Of the compounds of the general formulas (IX), (XI), (XII), (XIII), (XIV), (XV), (XVII) and (XVIII) can those with an amino, hydroxyl or carboxyl group can be obtained by previously viewing this group protects with a conventional protective group and after the implementation of the protective group according to known Procedure removed.

The compound of general formula (I) or a salt it can be processed according to conventional methods such as extraction, Crystallization, column chromatography and the like, isolated and cleaned.

If the compound of the invention as a drug or drug used, it will be more appropriate Combined with straps, which in conventional, pharmaceutical preparations are in use, and to tablets, capsules, powders, syrups, granules, Suppositories, ointments, injections and the like on conventional ones Processed way. The routes of administration that Dose instructions and the number of administrations can be varied appropriately depending on the symptoms Of the patients. Generally the connection administered orally or parenterally (e.g. by injection, Drip, rectal administration), in one Adults in an amount of 0.1 to 100 mg / kg / Day in one or more servings.  

In the following the invention with reference examples, Examples and preparation examples closer explained, without this being a limitation should. In the examples, the mixing ratio refers the mixed solvent in all cases on the volume. As a carrier in column chromatography a silica gel (Kieselgel 60, Art, 7734 der Merck Co.) used.

The following abbreviations are used in the examples:

Me = methyl
Et = ethyl
Boc = tert-butoxycarbonyl
Z = benzyloxycarbonyl
THP = 2-tetrahydropyranyl
+ = tert-butyl
TFA = trifluoroacetic acid
DMSO = N, N-dimethyl sulfoxide
D₂O = heavy water
sh or Sch = shoulder

Unless otherwise stated, the values for the IR spectrum are expressed in "cm ^-1 : ν _{C = O} ".

Reference Example 1

10.2 g of 60% sodium hydride are suspended in 500 ml of N, N-dimethylformamide. 55.0 g of di-tert-butylmalonate are added dropwise to the mixture over the course of 1 h, and the resulting mixture is stirred at the same temperature for 10 min. 48.0 g of methyl pentafluorobenzoate are added and the resulting mixture is stirred at room temperature for 2 h. The reaction mixture is added to a mixture of 1 liter of water and 40 ml of ethyl acetate. The resulting mixture is adjusted to pH 3 with 6N hydrochloric acid. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution in that order and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and the residue obtained is dissolved in 150 ml of trifluoroacetic acid. The resulting solution is stirred at room temperature for 20 h and the reaction mixture is concentrated under reduced pressure. The residue obtained is mixed with 200 ml of diethyl ether and 600 ml of water in this order. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution in that order and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and 50 ml of toluene are added to the residue obtained. The resulting mixture is refluxed for 1.5 h, the reaction mixture is concentrated under reduced pressure and n-hexane is added to the residue obtained. The resulting crystals are collected by filtration; 31.3 g (yield 55.5%) of methyl 4-carboxymethyl-2,3,5,6-tetrafluorobenzoate are obtained.
IR (KBr): 1725, 1720 (Sch).

The following connection is made in the same way:
Ethyl 4-carboxymethyl-2,3,5-trifluorobenzoate;
IR (KBr): 1710.

Reference Example 2

31.3 g of methyl 4-carboxymethyl-2,3,5,6-tetrafluorobenzoate are dissolved in 50 ml of diethyl ether. A diphenyldiazomethane / petroleum ether solution is added dropwise to the resulting solution at room temperature until the solution takes on a slightly reddish color. The resulting crystals are collected by filtration; 48.6 g (yield 95.7%) of methyl 4-diphenylmethoxycarbonylmethyl-2,3,5,6-tetrafuorboate are obtained.
IR (KBr): 1730.

The following connection is obtained in the same way:
Ethyl 4-diphenylmethoxycarbonylmethyl 2,3,5-trifluorobenzoate;
IR (KBr): 1730.

Reference example 3

48.6 ml of methyl 4-diphenylmethoxycarbonylmethyl-2,3,5,6-tetrafluorobenzoate are dissolved in 486 ml of N, N-dimethylformamide, and 3.54 g of p-formaldehyde and 61 mg of sodium methylate are added to the resulting solution in this order. The resulting mixture is stirred at room temperature for 2 hours. The reaction mixture is mixed with 300 ml of ethyl acetate and 800 ml of water in this order. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution in that order and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure. The residue obtained is purified by column chromatography (eluent: toluene / ethyl acetate = 10/1); 35.0 g (yield 67.0%) of methyl 4- (1-diphenylmethoxycarbonyl-2-hydroxyethyl) -2,3,5,6-tetra fluorobenzoate are obtained.
IR (neat): 1735.

The following connection is made in the same way:
Ethyl 4- (1-diphenylmethoxycarbonyl-2-hydroxyethyl) -2,3,5-trifluorobenzoate;
IR (neat): 1720.

Reference example 4

35.0 g of methyl 4- (1-diphenylmethoxycarbonyl-2-hydroxyethyl) -2,3,5,6-tetrafluorobenzoate are dissolved in 175 ml of methylene chloride and 7.9 g of methanesulfonyl chloride are added to the solution while cooling with ice. 16.8 g of triethylamine are added dropwise to the mixture within 10 minutes. The resulting mixture is stirred for 1 hour at the same temperature and 200 ml of water are added to the reaction mixture. The resulting mixture is adjusted to pH 1 in 2N hydrochloric acid. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution in that order and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure; 33.0 g (yield 97.9%) of methyl 4- (1-diphenylmethoxycarbonylvinyl) -2,3,5,6-tetrafluorobenzoate are obtained.
IR (pure). 1730.

The following connection is obtained in the same way:
Ethyl 4- (1-diphenylmethoxycarbonylvinyl) -2,3,5-trifluorobenzoate;
IR (neat): 1720.

Reference Example 5

3.08 g of ethyl 4- (1-diphenylmethoxycarbonylvinyl) -2,3,5-trifluorobenzoate are dissolved in 30 ml of diethyl ether and the resulting solution is treated with ice-cooling with a diazomethane-diethyl ether solution, prepared from 2.00 g of N -Methyl-N-nitrosourea. The resulting mixture is stirred for 12 hours at room temperature and the reaction mixture is concentrated under reduced pressure. The residue obtained is dissolved in 30 ml of toluene and the resulting solution is stirred at 60 ° C. for 1 h. The reaction mixture is concentrated under reduced pressure and the residue obtained is purified by column chromatography (eluent: toluene); 2.90 g (yield 91.2%) of ethyl 4- (1-diphenylmethoxycarbonyl-2-methylvinyl) -2,3,5-trifluorobenzoate are obtained.
IR (neat): 1715.

Reference example 6

3.2 g of methyl 4- (1-diphenylmethoxycarbonylvinyl) -2,3,5,6-tetrafluorobenzoate are dissolved in 15 ml of anisole, and 15 ml of trifluoroacetic acid are added to the resulting solution. The resulting mixture is stirred at room temperature for 1 h and the reaction mixture is concentrated under reduced pressure. The residue obtained is mixed with 20 ml of n-hexane and the resulting mixture is adjusted to pH 7.5 with saturated, aqueous sodium hydrogen carbonate solution. The aqueous layer is separated and mixed with 50 ml of ethyl acetate. The resulting mixture is adjusted to pH 1 with 6N hydrochloric acid. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution in that order and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure; 1.9 g (yield 95.0%) of methyl 4- (1-carboxyvinyl) -2,3,5,6-tetrafluorobenzoate are obtained.
IR (KBr): 1730, 1695.

The following connection is made in the same way:
Ethyl 4- (1-carboxyvinyl) -2,3,5-trifluorobenzoate;
IR (KBr): 1710, 1695 (Sch).

Reference Example 7

3.0 g of methyl 4- (1-carboxyvinyl) -2,3,5,6-tetrafluorobenzoate are dissolved in 20 ml of N, N-dimethylformamide and the resulting solution is stirred at 130 to 140 ° C. for 1.5 hours. The reaction mixture is concentrated under reduced pressure and the residue obtained is purified by column chromatography (eluent: toluene / n-hexane = 1/1); 2.0 g (yield 79.1%) of methyl 2,3,5,6-tetrafluoro-4-vinylbenzoate are obtained.
IR (neat): 1740.

The following connection is obtained in the same way:
Ethyl 2,3,5-trifluoro-4-vinylbenzoate;
IR (neat): 1720.

Reference Example 8

2.0 g of methyl 2,3,5,6-tetrafluoro-4-vinylbenzoate are dissolved in 10 ml of diethyl ether and the resulting solution is treated with ice-cooling using a diazomethane-diethyl ether prepared from 3.0 g of N-methyl-N-nitrosourea - solution. The mixture obtained is stirred for 2 hours at room temperature and the reaction mixture is concentrated under reduced pressure. The residue obtained is dissolved in 15 ml of xylene and the resulting solution is refluxed for 1 h. The reaction mixture is concentrated under reduced pressure; 2.1 g (yield 99.1%) of methyl 4-cyclopropyl-2,3,5,6-tetrafluorobenzoate are obtained.
IR (neat): 1735.

The following connection is made in the same way:
Ethyl 4-cyclopropyl-2,3,5-trifluorobenzoate;
IR (neat): 1715.

Reference Example 9

3.7 g of 60% sodium hydride are suspended in 330 ml of N, N-dimethylformamide and 20.2 g of trimethylsulfoxonium iodide are added to the resulting suspension while cooling with ice. The resulting mixture is stirred for 1 hour at room temperature and 33.0 g of methyl 4- (1-diphenylmethoxycarbonylvinyl) -2,3,5,6-tetrafluorobenzoate are added. The resulting mixture is stirred for 2 hours at the same temperature and 300 ml of ethyl acetate and 900 ml of water are added to the reaction mixture in this order. The resulting mixture is adjusted to pH 1 with 2N hydrochloric acid. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution in that order and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and the residue obtained is purified by column chromatography (eluent: toluene); 22.5 g (yield 66.1%) of methyl 4- (1-diphenylmethoxycarbonylcyclopropyl) -2,3,5,6-tetrafluorobenzoate are obtained.
IR (neat): 1735.

The following compounds are obtained in the same way:
Ethyl 4- (1-diphenylmethoxycarbonylcyclopropyl) -2,3,5-trifluorobenzoate; IR (KBr): 1725;
Ethyl 4- (1-diphenylmethoxycarbonyl-2-methylcyclopropyl) -2,3,5-trifluorobenzoate; IR (neat): 1715.

Reference example 10

22.5 g of methyl 4- (1-diphenylmethoxycarbonylcyclopropyl) -2,3,5,6-tetrafluorobenzoate are dissolved in 60 ml of anisole, and 80 ml of trifluoroacetic acid are added to the resulting solution. The resulting mixture is stirred at room temperature for 2 hours and the reaction mixture is concentrated under reduced pressure. The residue obtained is mixed with n-hexane. The resulting crystals are collected by filtration; 12.7 g (yield 88.8%) of methyl 4- (1-carboxycyclopropyl) -2,3,5,6-tetrafluorobenzoate are obtained.
IR (KBr): 1745, 1690.

The following connections are made in the same way:
Ethyl 4- (1-carboxycyclopropyl) -2,3,5-trifluorobenzoate; IR (KBr): 1715, 1685;
Ethyl 4- (1-carboxy-2-methylcyclopropyl) -2,3,5-trifluorobenzoate; IR (KBr): 1715, 1690.

Reference Example 11

500 mg of methyl 4- (1-carboxycyclopropyl) -2,3,5,6-tetrafluorobenzoate are about 20 sec using a burner heated directly to complete the decarboxylation.  The residue obtained is determined by column chromatography purified (eluent: toluene); one gains 210 mg (yield 49.5%) of methyl 4-cyclopropyl 2,3,5,6-tetrafluorobenzoate.

The following connection is obtained in the same way:
Ethyl 4-cyclopropyl-2,3,5-trifluorobenzoate.

The physical properties of these compounds are identical to those of Reference Example 8.

Reference example 12

9.0 g of methyl 4- (1-carboxycyclopropyl) -2,3,5,6-tetrafluorobenzoate are dissolved in 90 ml of N, N-dimethylformamide, and 4.0 g of ethyl chlorocarbonate and 3.7 are added to the resulting solution while cooling with ice g triethylamine in that order. The resulting mixture is stirred at the same temperature for 30 minutes and then 2.6 g of sodium azide are added while cooling with ice. The mixture obtained is stirred for 1 hour at the same temperature and 150 ml of ethyl acetate and 300 ml of water are added to the reaction mixture in this order. The mixture obtained is adjusted to pH 1 with 2 N hydrochloric acid. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution in that order and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and the residue obtained is dissolved in a mixture of 90 ml of dioxane and 8.1 g of benzyl alcohol. The resulting solution is refluxed for 1 h and the reaction mixture is concentrated under reduced pressure. The residue obtained is purified by column chromatography (eluent: toluene); 10.6 g (yield 86.9%) of methyl 4- (1-benzyloxycarbonyl aminocyclopropyl) -2,3,5,6-tetrafluorobenzoate are obtained.
IR (KBr): 1740, 1700.

The following connections are made in the same way:
Ethyl 4- (1-benzyloxycarbonylaminocyclopropyl) -2,3,5-trifluorobenzoate; IR (KBr): 1735, 1700;
Ethyl 4- (1-benzyloxycarbonylamino-2-methylcyclopropyl) -2,3,5-trifluorobenzoate; IR (neat): 1710.

Reference Example 13

(1) In 160 ml of methylene chloride, 15.65 g of ethyl 2,3,5-trifluoro-4-vinylbenzoate and added the obtained Solution with 11.40 g of bromine. The resulting is stirred Mixture at room temperature for 3 h and the reaction mixture was added with 100 ml of water. The organic layer is separated off with water and saturated, aqueous Washed sodium chloride solution in that order and dried over anhydrous magnesium sulfate. Man removes the solvent by distillation under reduced pressure Pressure and dissolves the residue obtained 100 ml methylene chloride. The resulting solution will with ice cooling with 20.7 g 1,8-diazabicyclo [5.4.0] undec- 7-en added and the mixture obtained at 1 h Room temperature stirred. The reaction mixture is added with 100 ml of water and make the resulting Mix with 2N hydrochloric acid to pH 1.5. The organic layer is separated off with water and saturated, aqueous sodium chloride solution in this Sequence washed and over anhydrous magnesium sulfate  dried. The solvent is removed by distillation under reduced pressure and dissolves the residue obtained in 30 ml of N, N-dimethylformamide.

(2) 1.90 g of 60% sodium hydride are suspended in 150 ml of N, N-dimethylformamide. 10.15 g of di-tert-butylmalonate are added dropwise to the resulting suspension over the course of 15 minutes while cooling with ice, and the mixture obtained is stirred at the same temperature for 1 hour. The N, N-dimethylformamide solution obtained in (1) above is added dropwise over 5 minutes while cooling with ice and the resulting mixture is stirred at room temperature for 12 hours. The reaction mixture is added to a mixture of 250 ml of ethyl acetate and 300 ml of water and the resulting mixture is adjusted to pH 3 with 2N hydrochloric acid. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution in that order and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and the residue obtained is purified by column chromatography (eluent: toluene); 12.69 g (42.0% yield) of ethyl 4- (2,2-di-tert-butoxycarbonylcyclopropyl) -2,3,5-trifluorobenzoate are obtained.
IR (KBr): 1720 (Sch), 1710.

Reference Example 14

18 ml of trifluoroacetic acid are added to 9.3 g of ethyl 4- (2,2-di-tert-butoxycarbonylcyclopropyl) -2,3,5-trifluoro benzoate and the mixture obtained is stirred for 12 hours at room temperature. The reaction mixture is concentrated under reduced pressure. The residue obtained is heated directly by means of a burner for about 20 seconds in order to complete the decarboxylation. The reaction mixture is mixed with 100 ml of diethyl ether and 200 ml of water in this order and the resulting mixture is adjusted to pH 9.5 with 10% aqueous sodium carbonate solution. The aqueous layer is separated off and mixed with 100 ml of diethyleter. The resulting mixture is adjusted to pH 1.5 with 2N hydrochloric acid. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution in that order and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure; 3.30 g (yield 54.7%) of ethyl 4- (2-carboxycyclopropyl) -2,3,5-trifluorobenzoate are obtained.
IR (KBr): 1725 (Sch), 1700.

Reference Example 15

1.00 g of ethyl 4- (2-carboxycyclopropyl) -2,3,5-trifluorobenzoate is dissolved in 10 ml of tert-butyl acetate and the resulting solution is mixed with 0.2 ml of 70% aqueous perchloric acid solution. The resulting mixture is stirred for 1 hour at room temperature and the reaction mixture is mixed with 40 ml of ethyl acetate and 20 ml of water in this order. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution in that order and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and the residue obtained is purified by column chromatography (eluent: n-hexane / toluene = 1/1); 0.81 g (yield 68.1%) of ethyl 4- (2-tert-butoxycarbonylcyclopropyl) -2,3,5-trifluorobenzoate is obtained.
IR (neat): 1720.

Reference Example 16

6.00 g of ethyl 4- (2-carboxycyclopropyl) -2,3,5-trifluorobenzoate are dissolved in 60 ml of anhydrous tetrahydrofuran, and 42 ml of a 1 M borane solution in tetrahydrofuran are added to the resulting solution while cooling with ice. The resulting mixture is stirred for 1.5 h at room temperature and mixed with a mixture of 100 ml of ethyl acetate and 100 ml of water. The resulting mixture is adjusted to pH 1 with 2N hydrochloric acid. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution in that order and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and the residue obtained is purified by column chromatography (eluent: toluene / ethyl acetate = 4/1); 4.40 g (yield 77.1%) of ethyl 4- (2-hydroxymethylcyclopropyl) -2,3,5-trifluorobenzoate are obtained.
IR (neat): 1720.

Reference Example 17

4.00 g of ethyl 4- (2-hydroxymethylcyclopropyl) -2,3,5-trifluorobenzoate are dissolved in 60 ml of methylene chloride, and 1.62 g of triethylamine and 1.84 g of methanesulfonyl chloride are added to the resulting solution in this order while cooling with ice. The resulting mixture is stirred for 2 hours at room temperature and 60 ml of water are added to the reaction mixture. The resulting mixture is adjusted to pH 1 with 2N hydrochloric acid. The organic layer is separated, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution in this order and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and the residue obtained is dissolved in 60 ml of N, N-dimethylformamide. 3.42 g of potassium salt of tert-butylmethyliminodicarboxylate are added to the resulting solution while cooling with ice and the mixture obtained is stirred at room temperature for 48 h. The reaction mixture is added to a mixture of 100 ml of ethyl acetate and 100 ml of water and the resulting mixture is adjusted to pH 1.5 with 2N hydrochloric acid. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution in that order and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and the residue obtained is purified by column chromatography (eluent: toluene / ethyl acetate = 20/1); 5.22 g (yield 82.9%) of ethyl 4- [2- (N-tert-butoxycarbonyl-N-methoxycarbonylaminomethyl) cyclopropyl] -2,3,5-trifluorobenzoate are obtained.
IR (neat): 1780, 1740 (Sch), 1715.

Reference Example 18

5.22 g of ethyl 4- [2- (N-tert-butoxycarbonyl-N-methoxycarbonylaminomethyl) cyclopropyl] -2,3,5-trifluorobenzoate are dissolved in 60 ml of ethanol, and 60 ml of 1N aqueous solution are added to the resulting solution Sodium hydroxide solution. The resulting mixture is stirred for 2 hours at room temperature, 60 ml of water are added to the reaction mixture and the resulting mixture is adjusted to pH 8 with 6N hydrochloric acid. Then 150 ml of ethyl acetate are added, the aqueous layer is separated off and 100 ml of ethyl acetate are added. The resulting mixture is adjusted to pH 2 with 6N hydrochloric acid. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution in that order and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure; 4.10 g (98.1%) of 4- (2-tert-butoxycarbonylaminomethylcyclopropyl) -2,3,5-trifluorobenzoic acid are obtained.
IR (KBr): 1720, 1700.

Reference Example 19

1.8 g of methyl 4- (1-benzyloxycarbonylaminocyclopropyl) -2,3,5,6-tetrafluorobenzoate are dissolved in a mixture of 14 ml of methanol and 14 ml of dioxane, and 14 ml of a 1N aqueous sodium hydroxide solution are added to the resulting solution. The resulting mixture is stirred for 1 h at room temperature and 50 ml of water are added to the reaction mixture. The resulting mixture is adjusted to pH 1 with 2N hydrochloric acid and 50 ml of ethyl acetate are added. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution in that order and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and n-hexane is added to the residue obtained. The resulting crystals are collected by filtration; 1.7 g (yield 97.7%) of 4- (1-benzyloxycarbonylaminocyclopropyl) -2,3,5,6-tetrafluorobenzoic acid are obtained.
IR (KBr): 1735.

The compounds listed in Table 2 are based on get same way.

in Table 2 those in the following formula:

Table 2

Reference Example 20

(1) (i) To 1.50 g of 4- (1-benzyloxycarbonylaminocyclopropyl) - 2,3,5,6-tetrafluorobenzoic acid is added to 4.66 g Thionyl chloride and 0.1 ml of N, N-dimethylformamide in this Sequence. The resulting mixture is 1 hour at 40 stirred to 50 ° C and the reaction mixture under reduced Concentrated pressure. The residue obtained is dissolved in 20 ml of toluene.

(ii) 470 mg of 60% sodium hydride are suspended in 10 ml of anhydrous tetrahydrofuran. 2.20 g of tert-butylethylmalonate are added dropwise to the resulting suspension over the course of 15 minutes with ice cooling, and the resulting mixture is stirred at the same temperature for 20 minutes. The reaction mixture is cooled to -20 ° C. and the toluene solution obtained in (1) (i) above is added dropwise over the course of 10 minutes at the same temperature. The resulting mixture is stirred at -20 to -10 ° C for 30 min and the reaction mixture is mixed with 20 ml of ethyl acetate and 20 ml of water in this order. The resulting mixture is adjusted to pH 1 with 2N hydrochloric acid. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution in that order and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and 10 ml of trifluoroacetic acid are added to the residue obtained. The resulting mixture is stirred for 12 hours at room temperature and the reaction mixture is concentrated under reduced pressure. The residue obtained is mixed with 20 ml of ethyl acetate and 20 ml of water in this order.
The organic layer is separated, washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated aqueous sodium chloride solution in this order and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and the residue obtained is purified by column chromatography (eluent: toluene / ethyl acetate = 20/1); 1.56 g (yield 87.6%) of ethyl 4- (1-benzyloxycarbonylaminocyclopropyl) -2,3,5,6-tetrafluorobenzoylacetate are obtained.
IR (KBr): 1710.

The following connection is obtained in the same way:
Ethyl 4-cyclopropyl-2,3,5,6-tetrafluorobenzoylacetate;
IR (neat): 1745, 1705.

(2) 7.50 g of 4- (1-benzyloxycarbonylaminocyclopropyl) -2,3,5-trifluorobenzoic acid are dissolved in 75 ml of anhydrous tetrahydrofuran, and 4.99 g of N, N'-carbonyldiimidazole are added to the resulting solution while cooling with ice. The resulting mixture is stirred for 1 hour at room temperature and mixed with 4.40 g of magnesium ethoxycarbonyl acetate. The resulting mixture is stirred at the same temperature for 20 hours and a mixture of 150 ml of ethyl acetate and 200 ml of water is added to the reaction mixture. The resulting mixture is adjusted to pH 1 with 2N hydrochloric acid. The organic layer is separated, washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated aqueous sodium chloride solution in this order and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and the residue obtained is purified by column chromatography (eluent: toluene / ethyl acetate = 5/1); 8.10 g (yield 90.6%) of ethyl 4- (1-benzyloxycarbonylaminocyclopropyl) -2,3,5-tetrafluorobenzoylacetate are obtained.
IR (neat): 1725, 1700 (Sch).

The compounds listed in Table 3 are based on get same way.

in Table 3 corresponds to that in the following formula:

Table 3

Reference Example 21

(1) 3.00 g of ethyl 4- (1-benzyloxycarbonylaminocyclopropyl) -2,3,5-trifluorobenzoylacetate are dissolved in 30 ml of benzene, and 3.69 g of N, N-dimethylformamide-dimethylacetal are added to the resulting solution. The resulting mixture is refluxed for 30 minutes and the reaction mixture is concentrated under reduced pressure. The residue obtained is dissolved in 15 ml of toluene and 518 mg of DL-2-amino-1-propanol are added to the resulting solution. The resulting mixture is stirred at room temperature for 17 h and the reaction mixture is concentrated under reduced pressure. The residue obtained is purified by column chromatography (eluent: toluene / ethyl acetate = 5/1); 3.09 g (yield 86.1%) of ethyl 2- [4- (1-benzyloxycarbonylaminocyclopropyl) -2,3,5-tetrafluorobenzoyl] -3- (2-hydroxy-1-methylethylamino) acrylate are obtained.
IR (KBr): 1690.

The compounds listed in Table 4 are based on get same way.

in Table 4 correspond to those in the following Formula:

(2) 500 mg of ethyl 4- (1-benzyloxycarbonylaminocyclopropyl) -2,3,5-trifluorobenzoylacetate are dissolved in 5 ml of benzene, 411 mg of N, N-dimethylformamide-dimethylacetal are added to the resulting solution and the resulting mixture is refluxed for 40 min . The reaction mixture is concentrated under reduced pressure and the residue obtained is dissolved in 5 ml of ethanol. 157 mg of 2-aminothioethanol hydrochloride and 139 mg of triethylamine are added to the resulting solution, and the resulting mixture is stirred at room temperature for 16 h. The reaction mixture is concentrated under reduced pressure and the residue obtained is purified by column chromatography (eluent: toluene / ethyl acetate = 5/1); 250 mg (yield 41.7%) of ethyl 2- [4- (1-benzyloxycarbonylaminocyclopropyl) -2,3,5-trifluorobenzoyl] -3- (2-mercaptoethylamino) acrylate are obtained.
IR (KBr): 1695.

Reference Example 22

300 g of ethyl 2- (4-cyclopropyl-2,3,5,6-tetrafluorobenzoyl) -3- (2-hydroxy-1-methylethylamino) acrylate are dissolved in 3 ml of N, N-dimethylformamide and the resulting solution is added with 130 mg potassium carbonate. The resulting mixture is stirred at 80 to 90 ° C. for 30 minutes and 20 ml of water are added to the reaction mixture. The resulting crystals are collected by filtration; 240 mg (yield 84.5%) of ethyl 7-cyclopropyl-5,6,8-trifluoro-1- (2-hydroxy-1-methylethyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylate are obtained .
IR (KBr): 1725, 1705.

The following connection is obtained in the same way:
Ethyl- (S) -7- (1-benzyloxycarbonylaminocyclopropyl) - 6,8-difluoro-1- [2- (N-tert-butoxycarbonyl-N-methylamino) - 1-methylethyl] -1,4-dihydro-4 -oxo-3-quinoline carboxylate;
IR (KBr): 1720, 1680.

Reference Example 23

300 mg of ethyl (S) -7- (1-benzyloxycarbonylaminocyclopropyl) - 6,8-difluoro-1- [2- (N-tert-butoxycarbonyl-N-methylamino) - 1- are added to 2 ml of trifluoroacetic acid while cooling with ice. methylethyl] -1,4-dihydro-4-oxo-3-quinolinecarboxylate and the resulting mixture is stirred for 2.5 hours at the same temperature. The reaction mixture is concentrated under reduced pressure and 20 ml of ethyl acetate and 10 ml of water are added to the residue in this order. The resulting mixture is adjusted to pH 8 with saturated, aqueous sodium hydrogen carbonate solution. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution in that order and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure; 240 mg (yield 96.0%) of ethyl (S) -7- (1-benzyloxycarbonylaminocyclopropyl) -6,8-difluoro-1- [2- (N-methylamino) -1-methylethyl] -1.4 are obtained dihydro 4-oxo-3-quinoline carboxylate.
IR (KBr): 1720, 1685.

example 1

170 mg of ethyl 7-cyclopropyl-5,6,8-trifluoro-1- (2-hydroxy-1-methylethyl) -1,4-dihydro-4-oxo is dissolved in 1.7 ml of N, N-dimethylformamide. 3-quinoline carboxylate and the resulting solution is mixed with 20 mg of 60% sodium hydride. The resulting mixture is stirred at 80 to 90 ° C for 15 h and the reaction mixture is added to a mixture of 5 ml of ethyl acetate and 5 ml of water. The resulting mixture is adjusted to pH 1.5 with 2N hydrochloric acid. The resulting crystals are purified by filtration; 63 mg (yield 39.1%) of ethyl 10-cyclopropyl-8,9-difluoro-3-methy-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [ 1,4] benzoxazin-6-carboxylate.
IR (KBr): 1725, 1690.

Example 2

240 mg of ethyl (S) - 7- (1-benzyloxycarbonylaminocyclopropyl) -6,8-difluoro-1- [2- (N-methylamino) -1-methylethyl] -1 are dissolved in 5 ml of N, N-dimethylformamide. 4-dihydro-4-oxo-3-quinoline carboxylate and the resulting solution is mixed with 80 g of potassium carbonate. The resulting mixture is stirred for 6 hours at room temperature and the reaction mixture is added to a mixture of 20 ml of ethyl acetate and 20 ml of water. The resulting mixture is adjusted to pH 3 with 2N hydrochloric acid. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution in that order and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and diethyl ether is added to the residue obtained. The resulting crystals are collected by filtration; 120 mg (yield 52.2%) of ethyl (S) -10- (1-benzyloxycarbonylaminocyclopropyl) - 9-fluoro-1,3-dimethyl-7-oxo-2,3-dihydro-1H, 7H-pyrido are obtained [1,2,3-de] [1,4] quinoxaline-6-carboxylate.
IR (KBr): 1715.

Example 3

3.07 mg of ethyl 2- [4- (1-benzyloxycarbonylaminocyclopropyl) -2,3,5-trifluorobenzyl] -3- (2-hydroxy-1-methylethylamino) acrylate and. Are dissolved in 25 ml of N, N-dimethylformamide adds 519 mg of 60% sodium hydride to the resulting solution while cooling with ice. The resulting mixture is stirred at room temperature for 18 hours and the reaction mixture is added to a mixture of 50 ml of ethyl acetate and 50 ml of water. The resulting mixture is adjusted to pH 1 with 2N hydrochloric acid. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution in that order and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure. The residue obtained is purified by column chromatography (eluent: toluene / ethyl acetate = 1/1); 760 mg (yield 26.9%) of ethyl 10- (1-benzyloxycarbonylaminocyclopropyl) - 9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de ] [1,4] benzoxazine-6-carboxylate.
IR (KBr): 1715.

The compounds listed in Table 5 are based on get same way. R² in Table 5 corresponds to that in the following formula:

Table 5

Example 4

2.07 mg of ethyl 2- [4- (1-benzyloxycarbonylaminocyclopropyl) -2,3,5,6-tetrafluorobenzoyl] - 3- (2-hydroxy-1-methylethylamino) is dissolved in 20 ml of N, N-dimethylformamide. -acrylate and the resulting solution is mixed with 1.17 g of potassium carbonate. The resulting mixture is stirred at 90 to 100 ° C for 3.5 h and the reaction mixture is added to a mixture of 40 ml of ethyl acetate and 40 ml of water. The resulting mixture is adjusted to pH 1.5 with 2N hydrochloric acid. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution in that order and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and diethyl ether is added to the residue obtained. The resulting crystals are collected by filtration; 1.40 mg (yield 72.9%) of ethyl 10- (1-benzyloxycarbonylaminocyclopropyl) - 8,9-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2 , 3-de] [1,4] benzoxazin-6-carboxylate.
IR (KBr): 1720.

The compounds listed in Table 6 are listed on get same way.

in Table 6 correspond to those in the following formula:

Table 6

Example 5

90 mg of ethyl 10- (1-benzyloxycarbonylaminocyclopropyl) - 9-fluoro-3- (2-tetrahydropyranyloxymethyl) - 7-oxo-2,3-dihydro-7H-pyrido [1,2,3- de] - [1,4] benzoxazin-6-carboxylate and the resulting solution is treated with 10 mg toluenesulfonic acid monohydrate. The resulting mixture is stirred for 4 hours at room temperature and the reaction mixture is concentrated under reduced pressure. The residue obtained is mixed with ethanol and the resulting crystals are collected by filtration; 47 mg (yield 61.0%) of ethyl 10- (1-benzyloxycarbonylaminocyclopropyl) 9-fluoro-3-hydroxymethyl-7-oxo-2,3-dihydro-1H-pyrido- [1,2,3- de] [1,4] benzoxazin-6-carboxylate.
IR (KBr): 1715.

Example 6

380 mg of ethyl 10- (1-benzyloxycarbonylaminocyclopropyl) -9-fluoro-3-hydroxymethyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] - [4] are suspended in 4 ml of methylene chloride. 1,4] benzoxazin-6-carboxylate and the resulting suspension is mixed with ice-cooling with 230 mg triethylamine and 260 mg methanesulfonyl chloride in this order. The resulting mixture is stirred at room temperature for 30 min and the reaction mixture is mixed with 10 ml of methylene chloride and 10 ml of water in this order. The resulting mixture is adjusted to pH 1 with 2N hydrochloric acid. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution in that order and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and 4.4 ml of benzene and 175 mg of 1,8-diazabicyclo [5,4,0] - undec-7-ene are added to the residue in this order. The resulting mixture is refluxed for 1 hour and the reaction mixture is added to a mixture of 20 ml of ethyl acetate and 20 ml of water. The resulting mixture is adjusted to pH 1 with 2N hydrochloric acid. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution in that order and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and the residue obtained is purified by column chromatography (eluent: toluene / ethyl acetate = 3/2); 240 mg (yield 71.0%) of ethyl 10- (1-benzyloxycarbonylaminocyclopropyl) - 9-fluoro-3-methylene-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de ] [1,4] benzoxazine-6-carboxylate.
IR (KBr): 1720, 1685.

Example 7

5 ml of trifluoroacetic acid are added to 570 mg of ethyl (S) - 10- (2-tert-butoxycarbonylcyclopropyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2 , 3-de] [1,4] benzoxazin-6-carboxylate and the resulting mixture is stirred for 1 h at room temperature. The reaction mixture is concentrated under reduced pressure and diethyl ether is added to the residue obtained. The crystals formed are collected by filtration; 460 mg (yield 92.9%) of ethyl (S) -10- (2-carboxycyclopropyl) - 9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1, 2,3-de] [1,4] benzoxazin-6-carboxylate.
IR (KBr): 1720.

Example 8

200 mg of ethyl (S) -10- (2-carboxycyclopropyl) -9-fluoro-2-methyl-7-oxo-2,3-dihydro-7H-pyrido are suspended in 4 ml of N, N-dimethylformamide [1, 2,3-de] [1,4] benzoxazin-6-carboxylate and the resulting suspension is mixed with 70 g of ethyl chlorocarbonate and 65 mg of triethylamine while cooling with ice. The resulting mixture is stirred at the same temperature for 15 min and 45 mg of sodium azide are added to the reaction mixture while cooling with ice. The resulting mixture is stirred at the same temperature for 1 h, and 20 ml of chloroform and 20 ml of water are added to the reaction mixture in this order. The resulting mixture is adjusted to pH 1 with 2N hydrochloric acid. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and 5 ml of dioxane and 115 mg of benzyl alcohol are added to the residue in this order. The resulting mixture is stirred at 100 ° C for 1.5 hours and the reaction mixture is concentrated under reduced pressure. The residue obtained is purified by column chromatography (eluent: chloroform / ethanol = 15/1); 160 mg (yield 64.0%) of ethyl (S) -10- (2-benzyloxycarbonylaminocyclopropyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2 , 3-de] - [1,4] benzoxazin-6-carboxylate.
IR (KBr): 1715.

Example 9

1 ml of a 30% strength hydrogen bromide / acetic acid solution is added to 52 mg of ethyl 10- (1-benzyloxycarbonylaminocyclopropyl) 9-fluoro-3-fluoromethyl-7-oxo-2,3-dihydro-7H-pyrido [1,2, 3-de] [1,4] benzoxazin-6-carboxylate and the resulting mixture is stirred for 1 h at room temperature. The reaction mixture is concentrated under reduced pressure and 10 ml of diethyl ether and 20 ml of water are added to the residue in this order. The aqueous layer is separated and 20 ml of ethyl acetate are added. The resulting mixture is adjusted to pH 8.5 with saturated, aqueous sodium hydrogen carbonate solution. The organic layer is separated, washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure, 35 mg (yield 90.8%) of ethyl 10- (1-aminocyclopropyl) 9-fluoro-3-fluoromethyl-7-oxo-2,3-dihydro-7H- pyrido [1,2,3-de] [1,4] benzoxazin-6-carboxylate.
IR (KBr): 1705.

Example 10

10 g of ethyl (S) -10- (1-benzyloxycarbonylaminocyclopropyl) 9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido are dissolved in 100 ml of acetic acid [1,2,3- de] [1,4] benzoxazin-6-carboxylate and 2 g of 5% palladium-on-carbon are added to the resulting mixture. The resulting mixture is stirred for 2 hours at atmospheric pressure in a stream of hydrogen. The reaction mixture is filtered and the filtrate is evaporated to dryness under reduced pressure. The residue obtained is mixed with 200 ml of methylene chloride and 200 ml of water in this order. The resulting mixture is adjusted to pH 7.7 with saturated, aqueous sodium hydrogen carbonate solution. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution in that order and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and diethyl ether is added to the residue obtained. The resulting crystals are collected by filtration; 6.43 g (yield 89.2%) of ethyl (S) -10- (1-aminocyclopropyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1 , 2,3-de] [1,4] benzoxazin-6-carboxylate.
IR (KBr): 1705.

Example 11

200 mg of ethyl (S) -10- (1-aminocyclopropyl) - 9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido are suspended in a mixture of 2 ml of acetonitrile and 4 ml of methanol [1,2,3-de] [1,4] benzoxazine-6-carboxylate. The resulting suspension is mixed with 230 mg of 37% aqueous formaldehyde solution and 73 mg of sodium cyanoborohydride in this order. The resulting mixture is stirred for 2 hours at room temperature and 0.1 ml of acetic acid is added to the reaction mixture. The resulting mixture is concentrated under reduced pressure and 20 ml of chloroform and 20 ml of water are added to the residue in this order. The resulting mixture is adjusted to pH 1 with 2N hydrochloric acid. The aqueous layer is separated and 20 ml of chloroform are added. The resulting mixture is adjusted to pH 7.5 with saturated, aqueous sodium hydrogen carbonate solution. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution in that order and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the residue obtained is purified by column chromatography (eluent: chloroform / ethanol = 20/1); 100 mg (yield 47.6%) of ethyl (S) - 10- [1- (N, N-dimethylamino) cyclopropyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro are obtained -7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylate.
IR (KBr): 1715.

Example 12

6.43 g of ethyl (S) -10- (1-aminocyclopropyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido are suspended in 33 ml of methylene chloride [1,2, 3-de] [1,4] benzoxazin-6-carboxylate and the resulting suspension is treated with ice cooling with 2.27 g of acetic anhydride. The resulting mixture is stirred for 1 h at room temperature and 30 ml of water are added to the reaction mixture. The resulting crystals are collected by filtration; 5.85 g (yield 81.1%) of ethyl (S) -10- (1-acetylaminocyclopropyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1 , 2,3-de] [1,4] benzoxazin-6-carboxylate.
IR (KBr): 1710, 1665.

Example 13

300 mg of ethyl (S) -10- (1-acetylaminocyclopropyl) - 9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H are dissolved in a mixture of 3 ml of anhydrous tetrahydrofuran and 1 ml of anhydrous hexamethylphosphoric triamide -pyrido [1,2,3-de] - [1,4] benzoxazin-6-carboxylate and add 30 mg of 60% sodium hydride to the resulting solution while cooling with ice. The resulting mixture is stirred for 30 minutes at the same temperature and 340 mg of methyl iodide are added while cooling with ice. The resulting mixture is stirred at room temperature for 1 h and 20 ml of chloroform and 20 ml of water are added to the reaction mixture in this order. The resulting mixture is adjusted to pH 2 with 2N hydrochloric acid. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution in that order and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the residue obtained is purified by column chromatography (eluent: chloroform / ethanol = 15/1); 100 mg (yield 19.2%) of ethyl (S) -10- [1- (N-acetyl-N-methylamino) cyclopropyl] -9-fluoro-3-methyl-7-oxo-2,3 are obtained dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylate.
IR (KBr): 1715, 1645.

Example 14

To 250 mg of ethyl 10-cyclopropyl-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylate 2.5 ml of a 1N aqueous sodium hydroxide solution, 2.5 ml of ethanol and 2.5 ml of dioxane in this order. The resulting mixture is stirred for 1.5 h at room temperature and 10 ml Was 12020 00070 552 001000280000000200012000285911190900040 0002003913245 00004 11901ser and 20 ml ethyl acetate are added to the reaction mixture in this order. The resulting mixture is adjusted to pH 3 with 2N hydrochloric acid. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and diethyl ether is added to the residue obtained. The resulting crystals are collected by filtration; 200 mg (yield 87.3%) of 10-cyclopropyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4 ] benzoxazin-6-carboxylic acid; Mp 263-265 ° C (recrystallized from chloroform-methanol).
IR (KBr): 1710
NMR (d₁-TFA) δ : 0.90-2.00 (7H, m), 2.10-2.70 (1H, m),
4.30-5.35 (3H, m), 7.91 (1H, d, J = 10.5 Hz),
9.26 (1H, s).

The compounds listed in Table 7 are listed on get same way.

in Table 7 correspond to those in the following formula:  

Table 7

Example 15

200 mg of 10- (1-benzyloxycarbonylaminocyclopropyl) - 8,9-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido are dissolved in 2 ml of N, N-dimethylformamide [1,2,3- de] [1,4] benzoxazin-6-carboxylic acid and the resulting solution is treated with 319 mg benzylamine. The resulting mixture is stirred for 4.5 h at 90 to 100 ° C and the reaction mixture is mixed with a mixture of 5 ml of ethyl acetate and 5 ml of water. The resulting mixture is adjusted to pH 1 with 2N hydrochloric acid. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution in that order and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and dimethyl ether is added to the residue obtained. The resulting crystals are collected by filtration; 110 mg (yield 46.4%) of 8-benzylamino-10- (1-benzyloxycarbonylaminocyclopropyl) - 9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3 -de] [1,4] benzoxazin-6-carboxylic acid.
IR (KBr): 1710.

The following connection is obtained in the same way:
8-benzylamino-10-cyclopropyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid; IR (KBr): 1695.

Example 16

230 mg of benzyl alcohol are dissolved in 2 ml of N, N-dimethylformamide and 85 mg of 60% sodium hydride are added to the resulting solution while cooling with ice. The resulting mixture is stirred for 30 min at room temperature and with ice cooling with 230 mg of 10- (1-benzyloxycarbonylaminocyclopropyl) - 8,9-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2 , 3-de] [1,4] benzoxazin-6-carboxylic acid was added. The resulting mixture is stirred at room temperature for 7 hours and the reaction mixture is added to a mixture of 15 ml of ethyl acetate and 15 ml of water. The resulting mixture is adjusted to pH 1 with 2N hydrochloric acid. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution in that order and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and the residue obtained is purified by column chromatography (eluent: chloroform / ethanol = 10/1); 73.0 mg (yield 24.6%) of 8-benzyloxy-10- (1-benzyloxycarbonylaminocyclopropyl) - 9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2 , 3-de] [1,4] benzoxazin-6-carboxylic acid.
IR (KBr): 1715.

The following connection is made in the same way:
8-benzyloxy-10-cyclopropyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid; IR (KBr): 1720.

Example 17

90.0 mg of 8-benzylamino-10- (1-benzyloxycarbonylaminocyclopropyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido is dissolved in 9 ml of acetic acid [1,2,3- de] [1,4] benzoxazin-6-carboxylic acid and the resulting solution is mixed with 80.0 mg of 5% palladium-on-carbon. The resulting mixture is stirred for 2 hours at room temperature and atmospheric pressure in a hydrogen stream and the reaction mixture is filtered. 5 ml of 2N hydrochloric acid are added to the filtrate and the resulting mixture is concentrated under reduced pressure. The residue obtained is mixed with ethanol. The resulting crystals are collected by filtration; 45.9 mg (yield 76.9%) of 8-amino-10- (1-aminocyclopropyl) - 9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2 , 3-de] [1,4] benzoxazin-6-carboxylic acid hydrochloride; Mp 277 to 281 ° C (recrystallized from ethanol-methanol).
IR (KBr): 1695.
NMR (d₁-TFA) δ : 1.30-2.20 (7H, m), 4.40-5.40 (3H, m), 9.25 (1H, s).

The compounds listed in Table 8 are listed on get same way.

in Table 8 correspond to those in the following Formula:

Table 8

Example 18

50 mg of 8-benzylamino-10-cyclopropyl-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4 are dissolved in 5 ml of acetic acid ] benzoxazin-6-carboxylic acid and the resulting solution is mixed with 50 mg of 5% palladium-on-carbon. The resulting mixture is stirred for 1.5 hours at room temperature and atmospheric pressure in a stream of hydrogen and the reaction mixture is filtered. The filtrate is evaporated to dryness under reduced pressure and ethanol is added to the residue obtained. The resulting crystals are collected by filtration; 19.7 mg (yield 50.5%) of 8-amino-cyclopropyl-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [ 1,4] benzoxazin-6-carboxylic acid; Mp <280 ° C (recrystallized from chloroform-ethanol).
IR (KBr): 1705
NMR (d₁-TFA) δ : 1.10-2.00 (7H, m), 2.10-2.60 (1H, m), 4.30-5.40 (3H, m), 9.32 (1H, s).

The following connection is made in the same way:
10-cyclopropyl-9-fluoro-8-hydroxy-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid; Mp 262-263 ° C (recrystallized from ethanol).
IR (KBr): 1720
NMR (d₆-DMSO) δ : 0.90-1.60 (7H, m), 1.80-2.40 (1H, m), 4.20-5.20 (3H, m), 8.93 (1H, s).

Example 19

2.5 ml of 6N hydrochloric acid are added to 90 mg of ethyl- (S) -10- [1- (N-acetyl-N-methylamino) cyclopropyl] - 9-fluoro-3-methyl-7-oxo-2,3 dihydro-7H-pyrido [1,2,3-de] - [1,4] benzoxazin-6-carboxylate and refluxed the resulting mixture for 4 h. The reaction mixture is concentrated under reduced pressure and ethanol is added to the residue obtained. The resulting crystals are collected by filtration; 50 mg (yield 62.5%) (S) -10- (1-methylaminocyclopropyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3 -de] - [1,4] benzoxazin-6-carboxylic acid hydrochloride; Mp 240 to 244 ° C (recrystallized from 6N hydrochloric acid-ethanol).
IR (KBr): 1720.
NMR (d₁-TFA) δ : 1.30-2.20 (7H, m), 3.03 (3H, s), 4.70-5.50 (3H, m), 8.10 (1H, d , J = 10.0 Hz), 9.46 (1H, s).

The compounds listed in Table 9 are listed on get same way.

in Table 9 correspond to those in the following formula:  

Table 9

Example 20

50 mg (S) -10- (2-benzyloxycarbonylaminocyclopropyl) - 9-fluoro-3-methyl-7-oxo-2,3-dihydro- are added to 0.5 ml of a 30% hydrogen bromide-acetic acid solution while cooling with ice. 7H-pyrido [1,2,3-de] [1,4] benzoxazin-6-carboxylic acid and the resulting mixture is stirred for 1 h at the same temperature. The reaction mixture is concentrated under reduced pressure and 5 ml of chloroform and 5 ml of water are added to the residue in this order. The aqueous layer is separated and the solvent is removed by distillation under reduced pressure. The residue obtained is mixed with diethyl ether and the resulting crystals are collected by filtration; 30 mg (yield 68.2%) (S) -10- (2-aminocyclopropyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3 -de] [1,4] benzoxazin-6-carboxylic acid hydrobromide; Mp 245 to 250 ° C (recrystallized from ethanol).
IR (KBr): 1700
NMR (d₁-TFA) δ : 1.10-2.30 (5H, m), 2.80-3.40 (1H, m), 3.50-4.10 (1H, m), 4.40 -5.50 (3H, m), 7.98 (1H, d, J = 10.0 Hz), 9.40 (1H, s).

The following connection is obtained in the same way:
(S) -10- (2-aminocyclopropyl) -9-fluoro-3-methylene-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazin-6 -carboxylic acid- hydrobromide; Mp 270 to 275 ° C (recrystallized from ethanol-methanol).
IR (KBr): 1705
NMR (d₁-TFA) δ : 1.30-2.30 (4H, m), 5.34 (2H, s), 5.95 (1H, d, J = 4.5 Hz), 6.28 ( 1H, d, J = 4.5 Hz), 8.04 (1H, d, J = 9.5 Hz), 9.55 (1H, s).

Example 21

730 mg (S) -10- (1-aminocyclopropyl) - 9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido- [1,2,3 -de] [1,4] benzoxazin-6-carboxylic acid hydrochloride and the resulting solution is mixed with 242 mg potassium hydroxide and 5.84 ml ethanol in this order. Then 0.19 ml of conc. Hydrochloric acid within 30 min at 60 ° C and then cools the resulting mixture to 20 ° C over 2 h. The mixture is stirred for a further 30 min and the resulting crystals are collected by filtration; 570 mg (yield 87.0%) of (S) -10- (1-aminocyclopropyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3 -de] [1,4] benzoxazin-6-carboxylic acid; Mp 269 to 271.5 ° C.
IR (KBr): 1705
NMR (d₁-TFA) δ : 1.30-2.20 (7H, m), 4.45-5.55 (3H, m), 8.06 (1H, d, J = 9.5 Hz), 9.42 (1H, s)
[ a ] = - 88.0 ° (c = 0.05, 0.05N aqueous sodium hydroxide solution).

Example 22

3.00 g of (S) -10- (1-aminocyclopropyl) - 9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3- de] [1,4] benzoxazin-6-carboxylic acid and the resulting suspension at 50 ° C with 996 mg methanesulfonic acid. The resulting mixture is cooled to 20 ° C. in the course of 2 h and the crystals formed are collected by filtration; 3.05 g (yield 78.1%) of a methanesulfonic acid salt of (S) - 10- (1-aminocyclopropyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido are obtained [ 1,2,3-de] [1,4] benzoxazin-6-carboxylic acid; Mp 263-265 ° C.
IR (KBr): 1710
NMR (D₂O) δ : 1.30-1.90 (7H, m), 2.84 (3H, s), 4.25-5.20 (3H, m), 7.53 (1; d, J = 10.0 Hz), 8.84 (1H, s).

Preparation example 1

With 50 g of (S) -10- (1-aminocyclopropyl) -9-fluoro-3-methyl-7- oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazin-6- carboxylic acid hydrochloride is mixed 49 g of crystalline Cellulose, 50 g corn starch and 1 g magnesium stearate and compresses the mixture into 1000 tablets of the flat type.

Preparation example 2

50 g corn starch are mixed with 100 g (S) -10- (1-aminocyclopropyl) - 9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid hydrochloride mixed. To make capsules, 1000 Capsules filled with the resulting mixture.

Claims (63)

1. pyridonecarboxylic acid derivative of the following general formula or a salt thereof wherein R¹ represents a hydrogen atom or a carboxyl protecting group; R² represents a hydrogen atom, a halogen atom, an alkoxy group, a protected or unprotected hydroxyl group, a protected or unprotected amino group, a protected or unprotected lower alkylamino group or a di-lower alkylamino group; R³ represents at least one group selected from the group consisting of hydrogen atoms, lower alkyl groups, protected or unprotected amino groups, protected or unprotected lower alkylamino groups, di-lower alkylamino groups, protected or unprotected carboxyl groups, protected or unprotected amino-lower alkyl groups, protected or unprotected lower alkylamino-lower alkyl groups, Di-lower alkylamino lower alkyl groups and protected or unprotected hydroxy lower alkyl groups; R⁴ represents at least one group selected from the group consisting of hydrogen atoms, lower alkyl groups, halogeno-lower alkyl groups, protected or unprotected hydroxy-lower alkyl groups, lower alkylidene groups and groups which form a cycloalkane ring with the carbon atom to which R⁴ is bonded; X represents a halogen atom; and A represents an oxygen or sulfur atom or a lower alkyl-substituted or unsubstituted imino group. 2. pyridonecarboxylic acid derivative or its salt according to claim 1, characterized in that R² for a hydrogen or halogen atom, a protected or unprotected hydroxyl group or a protected or unprotected amino group; and R³ at least one Group represents selected from the group consisting of from hydrogen atoms, lower alkyl groups or unprotected amino groups, protected or unprotected Lower alkylamino groups, di-lower alkylamino groups, protected or unprotected carboxyl groups and protected or unprotected amino-lower alkyl groups. 3. pyridonecarboxylic acid derivative or its salt according to claim 1 or 2, characterized in that R³ for at least one group is selected from the Group consisting of lower alkyl groups or unprotected amino groups, protected or unprotected lower alkylamino groups. 4. pyridonecarboxylic acid derivatives or its salt according to one of claims 1 to 3, characterized in that that R⁴ stands for at least one group from the group consisting of lower alkyl groups, Halogen-lower alkyl groups, lower alkylidene groups and Groups linked to the carbon atom to the R⁴ is to form a cycloalkane ring.   5. pyridonecarboxylic acid derivative or its salt according to Claim 1, characterized in that R³ for a Hydrogen atom or a protected or unprotected Amino group is at the 1-position of the cyclopropyl group is bound; R⁴ is a hydrogen atom or a Represents lower alkyl group; and A an oxygen or sulfur atom. 6. pyridonecarboxylic acid derivative or its salt according to Claim 1 or 5, characterized in that R² for a hydrogen atom, a halogen atom, a protected one or unprotected hydroxyl group or a protected or unprotected amino group. 7. pyridonecarboxylic acid derivative or its salt according to one of claims 1 to 6, characterized in that R¹ represents a hydrogen atom. 8. pyridonecarboxylic acid derivative or its salt according to one of claims 1 to 7, characterized in that that A represents an oxygen atom. 9. pyridonecarboxylic acid derivative or its salt according to one of claims 1 to 8, characterized in that that X represents a fluorine atom. 10. 10- (1-aminocyclopropyl) -9-fluoro-3-methyl-7-oxo 2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid or a salt thereof. 11. 8-amino-10- (1-aminocyclopropyl) -9-fluoro-3-methyl- 7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine- 6-carboxylic acid or a salt thereof.   12. 10- (1-aminocyclopropyl) -8,9-difluoro-3-methyl-7- oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazin-6- carboxylic acid or a salt thereof. 13. 10- (1-aminocyclopropyl) -9-fluoro-8-hydroxy-3-methyl- 7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine- 6-carboxylic acid or a salt thereof. 14. (S) -10- (1-aminocyclopropyl) -9-fluoro-3-methyl-7- oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazin-6- carboxylic acid or a salt thereof. 15. 10- (1-aminocyclopropyl) -9-fluoro-3-fluoromethyl-7- oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazin-6- carboxylic acid or a salt thereof. 16. (S) -10- (1-aminocyclopropyl) -3-ethyl-9-fluoro-7- oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazin-6- carboxylic acid or a salt thereof. 17. 10- (1-aminocyclopropyl) -9-fluoro-3-methylene-7- oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazin-6- carboxylic acid or a salt thereof. 18. 10 ′ - (1-aminocyclopropyl) -9′-fluoro-7′-oxo-spiro- [cyclopropane-1,3 ′ (2′H) - [7H] pyrido [1,2,3-de] [1,4] benzoxazine] - 6'-carboxylic acid or a salt thereof. 19. (S) -10- (1-amino-2-methylcyclopropyl) -9-fluoro-3- methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine- 6-carboxylic acid or a salt thereof.   20. (S) -10- [1- (N-methylamino) cyclopropyl] -9-fluoro- 3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazin-6-carboxylic acid or a salt thereof. 21. A process for producing a pyridonecarboxylic acid derivative represented by the following general formula or a salt thereof wherein R¹ represents a hydrogen atom or a carboxyl protecting group; R² represents a hydrogen atom, a halogen atom, an alkoxy group, a protected or unprotected hydroxyl group, a protected or unprotected amino group, a protected or unprotected lower alkylamino group or a di-lower alkylamino group; R³ represents at least one group selected from the group consisting of hydrogen atoms, lower alkyl groups, protected or unprotected amino groups, protected or unprotected lower alkylamino groups, di-lower alkylamino groups, protected or unprotected carboxyl groups, protected or unprotected amino lower alkyl groups, protected or unprotected lower alkylamino lower alkyl groups, Di-lower alkylamino lower alkyl groups and protected or unprotected hydroxy lower alkyl groups; R⁴ represents at least one group selected from the group consisting of hydrogen atoms, lower alkyl groups, halogeno-lower alkyl groups, protected or unprotected hydroxy-lower alkyl groups, lower alkylidene groups and groups which form a cycloalkane ring with the carbon atom to which R⁴ is bonded; X represents a halogen atom; and A represents an oxygen or sulfur atom or a lower alkyl-substituted or unsubstituted imino group, characterized in that a compound of the following general formula or a salt thereof wherein R¹, R³, R⁴, X and A have the meaning given above; R ^{2a represents} a hydrogen or halogen atom; and R⁵ represents a hydrogen atom or an amino protective group,
or a compound of the following general formula or a salt thereof where R ^2a , R³, R⁴, R⁵, X and A have the meaning given above and R ^{1a represents} a carboxyl protective group,
undergoes a ring closure reaction and, if necessary, converts the halogen atom present as R ^{2a of} the reaction product into a protected or unprotected hydroxyl group, a protected or unprotected amino group, a protected or unprotected lower alkylamino group or a di-lower alkylamino group by a conventional substitution reaction. 22. The method according to claim 21, characterized in that that R² represents a hydrogen or halogen atom, a protected or unprotected hydroxyl group or is a protected or unprotected amino group; and R³ represents at least one group selected from the group consisting of hydrogen atoms, lower alkyl groups, protected or unprotected amino groups, protected or unprotected lower alkylamino groups, Di-lower alkylamino groups, protected or unprotected carboxyl groups and protected or unprotected amino-lower alkyl groups. 23. The method according to claim 21 or 22, characterized in that that R³ represents at least one group, selected from the group consisting of lower alkyl groups, protected or unprotected amino groups and protected or unprotected lower alkylamino groups. 24. The method according to any one of claims 21 to 23, characterized in that R⁴ for at least one  Group stands, selected from the group consisting of Lower alkyl groups, halogen-lower alkyl groups, lower alkylidene groups and groups related to the carbon atom, to which R⁴ is bound, a cycloalkane ring form. 25. The method according to claim 21, characterized in that R³ is a hydrogen atom or a protected one or unprotected amino group which is attached to the 1- Position of the cyclopropyl group is bound; R⁴ for represents a hydrogen atom or a lower alkyl group; and A represents an oxygen or sulfur atom. 26. The method according to claim 25, characterized in that R² represents a hydrogen atom, a halogen atom, a protected or unprotected hydroxyl group or there is a protected or unprotected amino group. 27. The method according to any one of claims 21 to 26, characterized in that R¹ is a hydrogen atom. 28. The method according to any one of claims 21 to 23, characterized in that A represents an oxygen atom stands. 29. The method according to any one of claims 21 to 27, characterized in that X represents a fluorine atom. 30. The method according to claim 21, characterized in that 10- (1-aminocyclopropyl) -9-fluoro-3-methyl 7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine- 6-carboxylic acid or a salt thereof.   31. The method according to claim 21, characterized in that 8-amino-10- (1-aminocyclopropyl) -9-fluoro-3- methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine- 6-carboxylic acid or a salt thereof. 32. The method according to claim 21, characterized in that 10- (1-aminocyclopropyl) -8,9-difluoro-3-methyl 7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine- 6-carboxylic acid or a salt thereof. 33. The method according to claim 21, characterized in that that 10- (1-aminopropyl) -9-fluoro-8-hydroxy-3- methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine- 6-carboxylic acid or a salt thereof. 34. The method according to claim 21, characterized in that (S) -10- (1-aminocyclopropyl) -9-fluoro-3-methyl- 7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine- 6-carboxylic acid or a salt thereof. 35. The method according to claim 21, characterized in that 10- (1-aminocyclopropyl) -9-fluoro-3-fluoromethyl- 7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine- 6-carboxylic acid or a salt thereof. 36. The method according to claim 21, characterized in that (S) -10- (1-aminocyclopropyl) -3-ethyl-9- fluoro-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazin- 6-carboxylic acid or a salt thereof. 37. The method according to claim 21, characterized in that that 10- (1-aminocyclopropyl) -9-fluoro-3-methylene-  7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine- 6-carboxylic acid or a salt thereof. 38. The method according to claim 21, characterized in that that 10 '- (1-aminocyclopropyl) -9'-fluoro-7'-oxo- spiro- [cyclopropane-1,3 ′ (2′H) - [7H] pyrido [1,2,3-de] [1,4] benzoxazin] -6'-carboxylic acid or a salt thereof manufactures. 39. The method according to claim 21, characterized in that (S) -10- (1-amino-2-methylcyclopropyl) -9- fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazin-6-carboxylic acid or a salt thereof manufactures. 40. The method according to claim 21, characterized in that (S) -10- [1- (N-methylamino) cyclopropyl] -9- fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazin-6-carboxylic acid or a salt thereof manufactures. 41. The method according to any one of claims 21 to 40, characterized in that the ring closure reaction in Presence of a metal fluoride or a base. 42. The method according to any one of claims 21 to 41, characterized in that the ring closure reaction at 0 to 180 ° C is carried out. 43. Antibacterial agent, comprising as active ingredient a pyridonecarboxylic acid derivative of the following general formula or a salt thereof wherein R¹ represents a hydrogen atom or a carboxyl protecting group; R² represents a hydrogen atom, a halogen atom, an alkoxy group, a protected or unprotected hydroxyl group, a protected or unprotected amino group, a protected or unprotected lower alkylamino group or a di-lower alkylamino group; R³ represents at least one group selected from the group consisting of hydrogen atoms, lower alkyl groups, protected or unprotected amino groups, protected or unprotected lower alkylamino groups, di-lower alkylamino groups, protected or unprotected carboxyl groups, protected or unprotected amino-lower alkyl groups, protected or unprotected lower alkylamino-lower alkyl groups, Di-lower alkylamino lower alkyl groups and protected or unprotected hydroxy lower alkyl groups; R⁴ represents at least one group selected from the group consisting of hydrogen atoms, lower alkyl groups, halogeno-lower alkyl groups, protected or unprotected hydroxy lower alkyl groups, lower alkylidene groups and groups which form a cycloalkane ring with the carbon atoms to which R⁴ is attached; and A represents an oxygen or sulfur atom or a lower alkyl-substituted or unsubstituted imino group. 44. Antibacterial agent according to claim 43, characterized characterized in that R² is a hydrogen or Halogen atom, a protected or unprotected hydroxyl group or a protected or unprotected amino group stands; and R³ represents at least one group, selected from the group consisting of hydrogen atoms, Lower alkyl groups, protected or unprotected Amino groups, protected or unprotected Lower alkylamino groups, di-lower alkylamino groups, protected or unprotected carboxyl groups and protected or unprotected amino-lower alkyl groups. 45. Antibacterial agent according to claim 43 or 44, characterized in that R³ at least one Group represents selected from the group consisting of from lower alkyl groups, protected or unprotected Amino groups and protected or unprotected lower alkylamino groups. 46. Antibacterial agent according to one of the claims 43 to 45, characterized in that R⁴ at least represents a group selected from the group consisting of lower alkyl groups, halogen lower alkyl groups, Lower alkylidene groups and groups related to the carbon atom to which R⁴ is attached Form cycloalkane ring. 47. Antibacterial agent according to claim 43, characterized characterized in that R³ represents a hydrogen atom or a protected or unprotected amino group is attached to the 1-position of the cyclopropyl group is; R⁴ is a hydrogen atom or a lower alkyl group  means; and A is an oxygen or sulfur atom represents. 48. Antibacterial agent according to claim 43 or 47, characterized in that R² is a hydrogen atom, a halogen atom, a protected or unprotected one Hydroxyl group or a protected or unprotected Amino group means. 49. Antibacterial agent according to one of the claims 43 to 48, characterized in that R¹ for a Hydrogen atom. 50 Antibacterial agent according to one of the claims 43 to 49, characterized in that A is an oxygen atom means. 51. Antibacterial agent according to one of the claims 43 to 50, characterized in that X is a fluorine atom reproduces. 52. An antibacterial agent according to claim 43 comprising 10- (1-aminocyclopropyl) -9-fluoro-3-methyl-7-oxo 2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid or a salt thereof. 53. An antibacterial agent according to claim 43 comprising 8-amino-10- (1-aminocyclopropyl) -9-fluoro-3-methyl- 7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine- 6-carboxylic acid or a salt thereof.   54. An antibacterial agent according to claim 43 comprising 10- (1-aminocyclopropyl) -8,9-difluoro-3-methyl- 7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine- 6-carboxylic acid or a salt thereof. 55. An antibacterial agent according to claim 43, comprising 10- (1-aminocyclopropyl) -9-fluoro-8-hydroxy-3- methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine- 6-carboxylic acid or a salt thereof. 56. Antibacterial agent according to claim 43, comprising (S) -10- (1-aminocyclopropyl) -9-fluoro-3-methyl- 7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine- 6-carboxylic acid or a salt thereof. 57. An antibacterial agent according to claim 43 comprising 10- (1-aminocyclopropyl) -9-fluoro-3-fluoromethyl- 7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine- 6-carboxylic acid or a salt thereof. 58. An antibacterial agent according to claim 43 comprising (S) -10- (1-aminocyclopropyl) -3-ethyl-9-fluoro-7- oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazin-6- carboxylic acid or a salt thereof. 59. An antibacterial agent according to claim 43 comprising 10- (1-aminocyclopropyl) -9-fluoro-3-methylene-7- oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazin-6- carboxylic acid or a salt thereof.   60. An antibacterial agent according to claim 43, comprising 10 ′ - (1-aminocyclopropyl) -9′-fluoro-7′-oxo-spiro- [cyclopropane-1,3 ′ (2′H) - [7H] pyrido [1,2,3-de] [1,4] benzoxazin- 6'-carboxylic acid or a salt thereof. 61. An antibacterial agent according to claim 43 comprising (S) -10- (1-amino-2-methylcyclopropyl) -9-fluoro- 3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazin-6-carboxylic acid or a salt thereof. An antibacterial agent according to claim 43 comprising (S) -10- [1- (N-methylamino) cyclopropyl] -9-fluoro- 3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazin-6-carboxylic acid or a salt thereof. 63. Use of the pyridonecarboxylic acid defined in claim 1 Derivative or a salt thereof in the manufacture of a therapeutic agent for bacterial infectious diseases.